Evaluating the potential impact of mismatches outside the antigen recognition site in unrelated hematopoietic stem cell transplantation: HLA‐DRB1*1454 and DRB1*140101

Abstract

DNA sequencing of 268 individuals drawn from four US populations carrying two unresolved DRB1*14 alleles differing only outside the antigen recognition site identified DRB1*1454 in the majority. A database of 4222 human leukocyte antigen (HLA)-matched hematopoietic stem cell transplantation donor–recipient pairs was queried to determine the number likely mismatched for DRB1*140101/DRB1*1454 but matched for class I loci. A power calculation suggests that more than 88,000 transplants among European Americans will be needed to identify sufficient 7/8 allele-matched pairs to evaluate the impact of the DRB1*140101/DRB1*1454 mismatch on transplant outcome. Molecular modeling of the HLA-DR interaction with the T-cell receptor and with CD4 suggests that the amino acid substitution distinguishing the two alleles will have minimal impact on allorecognition.

A perspective on the selection of unrelated donors and cord blood units for transplantation

“…Consequently, HLA reports may designate a donor or recipient as having one of several possible alleles, all with the same antigen recognition site, for a given locus, and it is standard practice to accept identity of these donor and recipient assignments as a match. 32,33 Selection of HLA-mismatched donors or cord blood units How do I select the best partially matched unrelated donor or cord blood unit?…”

Next-generation sequencing: the solution for high-resolution, unambiguous human leukocyte antigen typing

“…Through the use of molecular modeling, DRB1* 1454 and DRB1*140101, which are identical in the ARS, were evaluated for differences in interactions with T-cell receptor and CD4 molecules. It was found that the single amino acid difference, located in the second domain of DRB1, would not influence ARS structure or interaction with T-cell receptors or CD4 [25]. However, this does not consider indirect allorecognition whereby the mismatched amino acid, as part of a peptide, may be presented by another self HLA molecule [26].…”

Effects of transmembrane region variability on cell surface expression and allorecognition of HLA-DP3

“…It has been shown that some of these polymorphisms can influence HLA surface expression by transcriptional regulation, alternative splicing or structural changes of the molecule [11][12][13], while others did not change the repertoire of bound peptides [14]. From the clinical side, a polymorphism in exon 3 of DRB1 Ã 14:01/14:54 was shown not to have a significant impact on the outcome of unrelated VUD-HSCT [15,16]. None of the to date available studies have directly addressed the effects of outside-the-groove polymorphisms on T cell alloreactivity, the most relevant factor for graft versus host disease (GvHD), graft versus tumor activity and engraftment after allogeneic HSCT.…”